tbuckley/cabot-search huggingface dataset:
ABC-12: Exploring the microbiome in patients (pts) with advanced biliary tract cancer (BTC) in a first-line study of durvalumab in combination with cisplatin/gemcitabine (cis/gem).
Authors: Mairead Geraldine McNamara, Hayley Timmins, Ashley Osborne, Rebecca Cox, Harpreet Singh Wasan, Pippa Corrie, Roopinder Gillmore, Shivan Sivakumar, Yuk Ting Ma, Olusola Olusesan Faluyi, Arvind Arora, Seema Arif, Jo Canham, Chris Hurt, Richard Hubner, John A Bridgewater, Richard Adams, Juan W. Valle
Journal: Journal of Clinical Oncology (2023)

TPS4183 Background: Durvalumab/cis/gem improved overall survival (OS) in pts with advanced BTC versus placebo/cis/gem (Oh et al. NEJM Evid 2022). Disruption of the microbiota may impair tumour response to immunotherapy and chemotherapy and a better understanding of its role in the efficacy of these therapeutics in advanced BTC is required. Methods: This is a multi-centre, single arm trial exploring the microbiome in pts receiving durvalumab 1500 mg intravenously (IV) Q3w, in combination with cis 25 mg/m 2 , gem 1000 mg/m 2 (Days 1 and 8, Q3w) up to 8 cycles, followed by durvalumab 1500 mg as monotherapy Q4w, until progression or intolerable toxicity. Pts with an ECOG performance status of ≤1 and histologically-proven BTC, including cholangiocarcinoma and gallbladder carcinoma, who have had no prior systemic chemotherapy for locally advanced or metastatic disease are eligible. Pts must provide a saliva and stool sample prior to commencement of durvalumab/cis/gem and at 18 weeks, or at progression (if earlier than 18 weeks). Taxonomic profiling via 16S Ribosomal ribonucleic acid gene sequencing will examine the differences in the diversity and composition of the pt gut microbiome. Pts must also have availability of a tumour biopsy. This study plans to recruit 70 pts from 10 UK centres (over 12 months). The primary objective is to determine the difference in baseline alpha diversity between “responders” (partial or complete response) and “non-responders” at 18 weeks (RECIST 1.1) in patients treated with durvalumab/cis/gem. Secondary objectives include investigation of the association between microbiome parameters and objective response rate, tumour control (partial + complete response + stable disease), progression-free and OS, and to investigate the interaction between treatment effect and microbiome parameters on clinical outcomes. The tumour biopsy will be used for research into the tumour microbiome and/or factors that may influence response to chemotherapy/immunotherapy, including, but not limited to tumour mutation burden, programmed cell death 1/programmed death-ligand 1 status, and microsatellite instability status. Clinical trial information: ISRCTN11210442 .
Targeting EZH2 to overcome the resistance to immunotherapy in microsatellite stable colorectal cancer: Results from the CAIRE study.
Authors: Lola Jade Palmieri, Sophie Cousin, Mariella Spalato, Jean Philippe Guégan, Alban Bessede, Simon Pernot, Antoine Italiano
Journal: Journal of Clinical Oncology (2023)

3599 Background: Profound epigenetic and transcriptomic changes induced by EZH2 in tumor cells and immune cells mobilize the elements of the TME, leading to immune-suppressive activity of solid tumors. Targeting EZH2 can enhance anti-tumor immunity by reshaping the tumor microenvironment (TME). The CAIRE study is first study investigating the impact of EZH2 inhibition in combination with immune checkpoint inhibitor in solid tumors. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of tazemetostat (800 mg BID) combined with durvalumab (1120 mg every 3 weeks) in patients with advanced microsatellite stable colorectal cancer. The primary endpoint was the disease control rate within 24 weeks after treatment onset defined as the proportion of patients with at least a tumor assessment showing connfirmed or unconfirmed complete response, confirmed or unconfirmed partial response or stable disease based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and safety using NCI-CTCAE v5.0. All patients underwent sequential blood and tissue sampling for translational studies. Results: Between July 2021, and June 2022, 47 pts were enrolled at Institut Bergonié (Bordeaux, Centre). Median age was 67.7 (range 39.6 – 84.0). Median number of previous treatment lines was 4: (range 1 – 6). The most common treatment related adverse events were grade 1/2 asthenia, nausea. No death was related to the treatment. Among the 34 pts for whom blinded central review of imaging was available for at least one imaging tumor assessment, best tumor response was confirmed partial response, stable disease and progressive disease in 1 (2.9%), 11 (32.3%) and 22 (64.7%) patients respectively. The disease control rate was 35.3% (95%CI 19.7 – 53.5). Conclusions: The CAIRE study met its first endpoint for disease control rate in patients with advanced colorectal cancer. Efficacy data on the whole cohort of patients and full biomarkers analyses will be presented at the meeting. Clinical trial information: NCT04705818 .
Real-world overall survival in second-line maintenance niraparib monotherapy vs active surveillance in <i>BRCA</i> wild-type patients with recurrent ovarian cancer.
Authors: Robert L. Coleman, Jessica Perhanidis, Linda Kalilani, Nicole M. Zimmerman, Amanda Golembesky, Kathleen N. Moore
Journal: Journal of Clinical Oncology (2023)

5592 Background: The Phase 3NOVA trial assessed niraparib versus placebo as a maintenance treatment (tx) for patients (pts) with recurrent ovarian cancer (OC) who were platinum-sensitive after ≥2 regimens; progression-free survival was the primary endpoint and overall survival (OS) was a secondary endpoint (NCT01847274). The aim of this real-world study was to compare OS in a breast cancer gene wild-type ( BRCAwt) population of pts with recurrent OC and who received second-line maintenance (2Lm) niraparib monotherapy or were under active surveillance (AS). Methods: This study used the US nationwide Flatiron Health de-identified electronic health record (EHR)-derived database. Pts diagnosed with epithelial OC between 1Jan2011–31May2021 who completed 2L therapy between 1Jan2017–2Mar2022 were eligible for inclusion. Pts were BRCAwt, had an ECOG PS score 0–1, epithelial histology, and platinum-sensitive disease with ≥6 months between end of first-line tx and start of 2L tx. Pts were assigned to 2Lm niraparib or AS cohorts based on their management following 2L non-maintenance therapy (≤120 days). Follow-up was measured from the index date (end of 2L non-maintenance therapy) until end of study (31May2022), last activity, or death, whichever came first. A target trial emulation cloned inverse probability of censoring weighting (IPCW) methodology was selected a priori to minimize bias. IPCW median OS and hazard ratios (HR) for 2Lm versus AS were estimated with Kaplan-Meier curves and Cox regression models. Results: Overall, 266 BRCAwt pts were included and received niraparib 2Lm (N=123) or were under AS (N=143). Across 2Lm and AS cohorts, prior to cloning and IPCW, 23.6% and 34.3% of pts were aged ≥75 years, and 26.0% and 16.8% had an EHR value for race as other than White, respectively. The majority of pts were from community practice (80.5% and 90.2%, respectively), had serous OC (79.7% and 81.1%) and had Stage III disease (53.7% and 60.8%). Homologous recombination deficiency status was unknown for 92.7% and 86.0% of pts in 2Lm and AS cohorts, respectively. Median follow-up for 2Lm and AS cohorts was 16.8 (Quartile [Q] 1, Q3: 10.4, 28.7) and 10.2 (Q1, Q3: 4.1, 23.7) months, respectively. IPCW median OS was 28.1 (95% confidence interval [CI]: 22.5, 43.2) and 21.5 (95% CI: 14.7, 27.0) months (HR: 0.63 [95% CI: 0.45, 0.88]) for niraparib 2Lm and AS cohorts, respectively and survival rates at 24 months were 58.2% (95% CI: 47.5, 67.6) and 46.1% (95% CI: 33.6, 57.7). Conclusions: This analysis provides real-world data on OS among pts with OC receiving niraparib 2Lm or under AS in the 2L setting following chemotherapy. Funding: GSK study (219306). Editorial support was provided by Fishawack Health, funded by GSK.
Genomic profiling of biliary tract carcinomas by their location.
Authors: Zoran Gatalica, David K. Edwards, Cynthia A. Flannery, David W. Hall, Jess R Hoag, Nishitha Therala, Janine R. LoBello, Snehal Govind Thakkar, Gargi D. Basu, Maen Abdelrahim
Journal: Journal of Clinical Oncology (2023)

e16175 Background: Historically, biliary tract cancers have had a poor prognosis. Genomic profiling allows identification of alterations in genes with FDA-approved matched therapies either in these cancers ( FGFR2/3 fusions, certain IDH1 missense mutations), in all solid tumors (e.g. BRAF V600E mutations), or in other cancers (e.g. BRCA1/2 loss-of-function mutations) that could inform treatment. Here we examine the frequency of matched therapies in biliary tract carcinomas and the association with tumor location. Methods: All biliary tract carcinoma patient samples receiving the OncoExTra assay between April 2018 and November 2022 were included. The assay uses tumor-normal, whole-exome, whole-transcriptome sequencing to identify genomic alterations. Alterations in genes with FDA-approved matched therapies in any cancer, with matched clinical trials, or with evidence in cancer guidelines or the literature for possible matched therapies were recorded. Results: A total of 155 patient samples were processed: 92 intrahepatic CCA, 34 gall bladder carcinomas, 9 extrahepatic CCA, and 20 ampulla of Vater carcinomas. Targetable alterations were found in 153 (98.7%) samples; 31 (20.3%) had FDA-approved matched therapies, including 5 (3.3%) with microsatellite unstable and/or tumor mutational burden-high (eligible for immunotherapy) and 7 (4.6%) homologous recombinational repair deficient. Alterations of several genes showed a significant association with tumor type (Table). Cancers in the ampulla of Vater were enriched for KRAS, APC and ARID2 alterations; TP53 alterations were less frequent in biliary tract/intrahepatic cancers. Among the 15 FGFR1/2/3 alterations, there were 3 amplifications (1 FGFR1, 1 FGFR2, 1 FGFR3), 3 missense FGFR2 mutations, and 9 FGFR2 fusions. Conclusions: Comprehensive genomic profiling of biliary tract cancers identifies numerous targetable alterations. The distribution of altered genes varies, suggesting that appropriate therapies may differ by location, reflecting different lineage types. [Table: see text]
Sintilimab combined with bevacizumab biosimilar as a conversion therapy in potentially resectable intermediate-stage hepatocellular carcinoma (HCC): Updated results of a phase II trial.
Authors: Huichuan Sun, Xiaodong Zhu, Qiang Gao, Shuang-Jian Qiu, Ying-Hong Shi, Xiao-Ying Wang, Xiao-Wu Huang, Xin-Rong Yang, Yuan Ji, Yanrui Pang, Yi-Feng He, Yong-Feng Xu, Jie Liu, Mingquan Sun, Mei-Ling Li, Jin-Jin Zhu, Ying-Hao Shen, Cheng Huang, Jian Zhou, Jia Fan
Journal: Journal of Clinical Oncology (2023)

e16220 Background: The combination of Sintilimab (a PD-1 antibody) and bevacizumab (bev) biosimilar improved progression-free survival and overall survival in unresectable or advanced HCC as compared with sorafenib in ORIENT-32 study and was approved as first-line treatment for unresectable HCC in China. We assessed the efficacy and safety of the combination therapy as conversion therapy for potentially resectable intermediate-stage HCC. Methods: Treatment-naïve patients (pts) with potentially resectable intermediate stage (BCLC stage B) HCC were enrolled in this phase II trial (NCT04843943). Eligible pts received sintilimab (200 mg, IV, D1) and bev (15 mg/kg, IV, D1) per 3 weeks. Tumor response and resectability were assessed every 6 weeks per RECIST v1.1. Pts with evaluations of partial response (PR) or at least two consecutive stable disease (SD) and eligible for R0 resection were referred for hepatectomy, then continued with sintilimab/bev for at most 12 months. Primary endpoints were event-free survival (EFS) (time from study enrollment to tumor progression, disease recurrence after surgery, or death from any cause) and treatment safety. Secondary endpoints included R0 resection rate, pathologic response, objective response rate (ORR), and disease control rate (DCR). Results: At data cutoff on Feb 7, 2023, 30 pts with BCLC-B stage HCC were enrolled. Of them, 25 pts (83.3%) were up-to-7 criteria out. The median follow-up time was 15.3 months (interquartile range [IQR] 13.8-17.6). ORR and DCR were 26.7% and 90.0% (8 PR and 19 SD). 17 pts (56.7%) met the pre-designated criteria for hepatectomy and received liver resection, including 7 pts were evaluated as PR and 10 as SD before surgery. The median time from initiation of sintilimab/bev to liver resection was 4.3 months (IQR 2.3-5.6). No postoperative mortality was observed. 2 pts had a pathological complete response. Median EFS was 13.8 months (95%CI, 10.3-17.3), and the 6-month and 12-month EFS rates were 76% and 60%, respectively. 3 pts died, and OS data was not mature. Most treatment-related AEs (TRAE) were grade 1-2, and grade 3/4 TRAEs occurred in 7 pts (23.3%). 9 serious adverse events occurred, and 3 of them were treatment associated. Conclusions: For pts with potentially resectable intermediate-stage HCC, sintilimab/bev in combination with liver resection was safe and may improve long-term survival. Clinical trial information: NCT04843943 .
Genomic landscapes of early-onset versus average-onset colorectal cancer populations.
Authors: Michael H. Storandt, Qian Shi, Cathy Eng, Christopher Hanyoung Lieu, Melissa Conrad Stoppler, Thomas J. George, Elizabeth Mauer, Emily Teslow, Amit Mahipal, Zhaohui Jin
Journal: Journal of Clinical Oncology (2023)

3536 Background: Early-onset colorectal cancer (eoCRC, initial CRC diagnosis at age &lt; 50 years) has been increasing in the past two decades especially in Western countries. This study evaluates somatic and germline profiles in eoCRC compared to average-onset CRC (aoCRC, initial CRC diagnosis at age ≥ 50 years). Methods: This is a retrospective, cross-sectional study utilizing data from de-identified records of colorectal cancer patients tested with the Tempus xT assay from 2017 to 2022. Briefly, the assay is a targeted panel that detects single nucleotide variants, insertions and/or deletions, and copy number variants in 598-648 genes, as well as chromosomal rearrangements in 22 genes with high sensitivity and specificity. Baseline characteristics and immunologic markers were compared between eoCRC and aoCRC by Wilcoxon Rank Sum or Chi-squared test (reporting p-values). Somatic and germline mutations were compared between two age groups with false discover rate adjustments (reporting q-values). Results: In this study, 2,379 eoCRC and 8,627 aoCRC patients were included, with the majority diagnosed with stage IV disease. Additionally, germline alterations were assessed on a subset of 6,311 patients with tumor/normal match testing (eoCRC = 1,413 and aoCRC = 4,898). Left-sided primaries were more common in eoCRC (85% left/rectum in eoCRC vs. 75% left/rectum in aoCRC (p &lt; 0.001), and rates of microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) were lower compared to aoCRC (4.2% vs. 6.8%, p &lt; 0.001). eoCRC has a unique somatic mutation profile compared to aoCRC. A higher prevalence of germline mutations was observed in eoCRC overall (6.9% vs. 5%, p = 0.006); however, no statistically significant differences were observed in individual germline genes compared to aoCRC, likely due to relatively small numbers. Conclusions: eoCRC has a unique mutational profile and presence of germline mutations in 6.9% of eoCRC, indicating a potential role for universal germline testing in CRC. [Table: see text]
First clinical study reporting safety and outcomes of high dose oxaliplatin use in PIPAC for colorectal peritoneal carcinomatosis.
Authors: S.P. Somashekhar, Ashwin K. Rajgopal, Susmita Rakshit, Aaron marian Fernandes, Darshan Patil, Rohit Kumar
Journal: Journal of Clinical Oncology (2023)

e15606 Background: PIPAC in inoperable colorectal peritoneal carcinomatosis has showed better oncological outcomes at existing doses of 92mg/m2. However the maximum dose that can be used and its clinical outcomes is not defined yet. Methods: PIPAC was done at dose 120 mg /m2 oxaliplatin which was established from a phase 2 study. The patient demographics, perioperative findings, adverse events, and outcomes were prospectively recorded. Response rate was graded as Peritoneal Regression Grading Score (PRGS). QoL of the patients was studied according to the EORTC QLQ - C30 score. Results: 42 PIPAC administrations were performed in 15 patients. The median hospital stay was 1.5 day (1-3 day). CTCAE grade 3 was observed in 5 patients, for abdominal pain and nausea, grade 3 fatigue in 4 patients. Transient increase in C- reactive protein was seen in 8 patients, haematological, renal and hepatic functions were not impaired in any patients except for mild transient elevation in AST and ALT levels in 7 patients. 12 patients completed 3 cycles of PIPAC. Of the 15 patients, 3 had complete response (PRGS 1) and 8 had major (PRGS 2), 3 had minor response (PRGS 3). There was improvement in functional scale, symptom scale and overall global health status for all patients. Conclusions: PIPAC can be performed safely at dose of oxaliplatin 120mg/m2. There is better objective &amp; pathological response with this dose with no major complications or side effects to the patients. There is also improvement in quality of life. This dose should be new standard of care for further studies.
Trastuzumab (T) plus gemcitabine-cisplatin (GC) for treatment naïve HER2 positive biliary tract adenocarcinomas (BTC): A multicentre open-label, phase II study (TAB).
Authors: Vikas S. Ostwal, Sarika Mandavkar, Prabhat Ghanshyam Bhargava, Sujay Srinivas, Chaitali Nashikkar, Omshree Shetty, Rajiv Kumar Kaushal, Subhash Yadav, Aekta Shah, Akshay Dwarka Baheti, Suman Kumar Ankathi, Daksha Mehta, Akhil Kapoor, Mahesh Goel, Shraddha Patkar, Deepali Chaugule, Anant Ramaswamy
Journal: Journal of Clinical Oncology (2023)

4089 Background: HER2 over-expression or amplification is seen in 4%-16% of BTCs and is a therapeutic target of interest. Gemcitabine-cisplatin (GC) is one of the standard regimens of choice in advanced BTCs. We aimed to evaluate the clinical activity of GC plus anti-HER2 antibody trastuzumab as initial treatment in HER2-positive BTC. Methods: This study was an investigator-initiated, open-label, single-arm, multi institutional, phase II trial in patients (pts) aged 18 years or older with HER2-positive (defined as IHC 3+ or IHC 2+ and FISH positive), treatment naïve BTCs. Patients received GC (Gem 1000 mg/m2 IV and Cisplatin 25mg/m2 IV on day 1 and 8, q 3 weeks) combined with Trastuzumab at 8mg/kg as initial dose followed by 6mg/kg q 3 -weekly till disease progression (PD) or unacceptable toxicities. The primary end-point of the study was an improvement in 6-month progression free survival (PFS) from 40% (historical cohort) to 60% in the study arm. Next generation sequencing to evaluate HER2 and other mutations was conducted on the tissue samples of the patients screened for this study. Results: From March 2020 to August 2022, of the 876 patients were screened for HER2 status, 118 (13.4%) were found to have HER2 positive status and 90 of them were enrolled into the study. A majority of patients had GBC (95.6%) and at-least 2 sites of metastatic disease beyond primary (77.8%). With a median follow up of 8.5 months, 72 patients had PD and the median PFS was 7.95 months (95% CI: 6.84 -9.06; median overall survival (OS) was 9.95 months (95% CI: 9.25 – 10.66). Partial responses (PR) were seen in 8 patients (8.9%) and 61 had stable disease (67.7%) for a disease control rate of 76.6%. Common chemotherapy-related grade 3 or 4 adverse events were anemia [26 (28.9%)], neutropenia [18(20%)] and thrombocytopenia [8(8.9%)] while one patient has Trastuzumab related asymptomatic fall in cardiac ejection fraction (&gt;=10%). The presence of isolated TP53 mutations predicted for inferior PFS compared to patients with other mutations (TERT promoter, HER2, PIK3CA etc) or no detected mutations (6.51 months vs. 12.02 months vs. 10.58 months; p&lt;0.001). Conclusions: The combination of GC and trastuzumab shows near doubling of survival in treatment naive HER2 positive BTC in a prospective manner for the first time and sets the stage for a larger phase III trial with the combination. Evaluating mutations like TP53, HER2, TERT promoter and PIK3CA along with HER2 testing could be considered as a preferred modality to select these patients for anti HER2 therapy. Clinical trial information: CTRI/2019/11/021955 . [Table: see text]
Anemia in patients aged ≥75 years with metastatic clear cell renal cell carcinoma: An important IMDC prognostic factor for systemic therapy.
Authors: Ryuichi Mizuno, Nobuyuki Tanaka, Mototsugu Oya
Journal: Journal of Clinical Oncology (2023)

e16524 Background: Due to an increase in life expectancy, the incidence of metastatic renal cell carcinoma (mRCC) in patients aged ≥75 years has been increasing. In this study we investigated the characteristics before treatment and the outcomes of systemic therapies for patients aged ≥75 years with mRCC and compared the results with those for patients aged &lt; 75 years in order to determine whether differences in age influenced survival. Methods: A total of 206 consecutive Japanese patients with mRCC, including 47 patients aged ≥75 years, who received systemic therapy were included. Clinical data from medical records were retrieved and analyzed retrospectively. Differences of several factors between the two groups were analyzed by the Chi-squared and Wilcoxon tests. Matching and balancing of the empirical distributions were performed by logistic regression analyses. Survival analyses were determined using a Kaplan–Meier method, and analyzed with a log-rank test. P values less than 0.05 were judged as statistically significant. Results: Elderly patients categorized as favorable risk group based on the International Metastatic RCC Database Consortium (IMDC) stratification system were significantly lower (p = 0.0241). Among IMDC risk factors, the rate of anemia was significantly higher in elderly patients (p = 0.006). No statistically significant benefit in PFS for first (p = 0.2183) and second line treatment (p = 0.2219) was observed, whereas improvements in OS (p = 0.0082) as well as CSS (p = 0.0083) were seen in patients aged &lt; 75 years. Furthermore, mRCC patients aged ≥75 years tend to receive BSC instead of second line active treatment. To determine the impact of higher rates of IMDC intermediate/poor risk group in patients aged ≥75 years, we used propensity score matching using IMDC risk stratification to minimize potential bias. After propensity score matching, the well-matched 46 patients in each group demonstrated similar OS (p = 0.203) and CSS (p = 0.172). Conclusions: For mRCC patients aged ≥75 years, a higher proportion of base line anemia, which resulted in higher rates of IMDC intermediate/poor risk, would be responsible for shorter OS/CSS. In addition, mRCC patients aged ≥75 years tend to receive BSC instead of second line active treatment. Overcoming under-treatment in elderly patients might help to prolong survival in mRCC.